GENOMIC INSTABILITY AND CANCER GENETICS PROGRAM PROJECT SUMMARY/ABSTRACT The Genomic Instability and Cancer Genetics (GICG) Program is organized around the central concepts that cancer results from the accumulation of genomic alterations, and that well-defined descriptions of DNA repair mechanisms, cancer genomes, and gene expression landscapes can reveal the vulnerability of cancer to interventions. The overall goal is to determine how cells maintain the integrity of their genomes, define the landscapes of cancer genomes, and facilitate identification of biomarkers and therapeutic targets. The GICG Program is composed of a highly qualified team of 44 members of diverse and complementary expertise from 19 Departments, 7 Schools, and 2 Universities. Our research is funded by a total of $11.2 million annual direct funding, including $8.6 million cancer-relevant funding ($3 million annual direct funds from NCI), 22 fully-cancer focused and NIH R01 equivalent research grants from 17 different and independent PD/PIs, and 11 multi-PI awards. Productivity and collaboration within GICG is evident from the significantly increased cancer-focused publications (586, up from 388 in 2004-2010), 30% collaborative publications (up from 25% in 2004-2010) including those that are 17% intra- and 24% inter-programmatic (up from 9.3% and 20% in 2004-2010), 54% inter-institutional collaborative publications, and 28% of the publications are in top tier journals. Achievements toward the scientific goals are exemplified by the demonstration of a distinct role of BRCA1- PALB2 interaction in supporting conserved homologous combinational DNA repair and suppressing mutagenic DNA single strand annealing, identification that the Pif1 DNA helicase overcomes replication fork blocks at G4-rich regions, mechanistic elucidation of the gain-of-function p53 mutations in the regulation of cancer metabolism and metastasis, discovery of two subtypes of oncocytomas with distinct mutational signatures, and the discovery of increased mutation burden at the nuclear peripheral lamina chromosome domains due to genome wide DNA repair heterogeneity. Translation and inter-programmatic interaction are reflected by the contribution of GICG to the genomic analysis of tumors with the application of state-of-the- art cancer genomic approaches as an integrated part of our clinical practice of Precision Medicine, new clinical trials based on the understanding of genomic instability and cancer mutation burden, and laboratory inquiries of new hypotheses emanating from the Clinical Investigations and Precision Therapeutics (CIPT) Program.